UC Davis

Our body regulates the macronutrient selection according to our nutritional status. Fibroblast growth factor 21 (FGF21) is hepatokine mainly released in response to protein restriction. Recent research suggests that FGF21 acts in brain to increase dietary protein intake and reduce sucrose consumption. However, most studies investigating the behavioral effects of FGF21 have primarily focused on males but not females. Additionally, the neurocircuit mechanisms underlying these behavioral changes have not yet been fully elucidated although previous work points towards hedonic rather than homeostatic pathways. To address these questions, we first examined the behavioral effects of pharmacologic FGF21 on sucrose consumption and dietary protein intake in female mice. Similar to previous finding in males, FGF21 administration decreased sucrose intake and increased dietary protein consumption by acting on the nervous system. We then hypothesized that a history of protein restriction would increase the palatability of a protein-rich snack and reduce the palatability of a sucrose ‘dessert’ in sated mice. As expected, FGF21 induced by 3-day protein restriction was sufficient and necessary to enhance the consumption of a protein-rich snack in sated males. However, this increased consumption was not observed in females, who exhibited a less robust induction of FGF21. The sex-dependent behavior may depend on sex differences in FGF21 secretion and/or FGF21 sensitivity. Besides the protein-rich snack, we demonstrated that chronic protein restriction decreased the consumption of a sucrose ‘dessert’ in sated mice despite no effect observed in response to short-term protein restriction. The dopamine release in nucleus accumbens (NAc) was significantly reduced in chronically protein-restricted mice during the sucrose consumption. Moreover, protein restriction inhibited the sucrose-conditioned place preference, accompanied by a significant decrease in neuronal activation of the NAc core. These findings advance our mechanistic understanding of how dietary protein restriction decreases the consumption of sweets—by inhibiting the incentive salience of a sucrose reward, together with reduced sucrose-evoked dopamine release in NAc. In summary, this dissertation enhances our understanding of the behavioral effects of FGF21 in both sexes and highlights the role of FGF21 and dietary protein restriction in regulating the hedonic value of food and dopaminergic signaling in NAc.